Colon cancer is the second most common cancer in the U.S. and kills more than 50,000 people each year, but it is also one of the most preventable cancers. Screening provides the best prevention. With regular screening, precancerous polyps can be detected and removed, thus preventing the development of colon cancer. Current screening tests such as sigmoidoscopy, colonoscopy and detection of fecal occult blood have significant problems, which have stimulated the search for more specific non-invasive tests for the early detection of colorectal cancers. In recent Serial Analysis of Gene Expression (SAGE) studies performed on normal, adenomatous and cancerous colonic epithelium, the enzyme Renal Dipeptidase (RDP) was found to be overexpressed in both benign and malignant tumor compared with normal colonic epithelium.1
RDP is a glycosylphosphatidyl inositol-anchored enzyme whose major site of expression is the epithelial cells of the proximal tubule of the kidney. The enzyme has been extensively analyzed with respect to its catalytic mechanism and inhibition kinetics by variety of synthetic inhibitors. RDP is unique among the dipeptidases in that it can cleave amine bonds in which the COOH-terminal partner is a D-amino acid, providing an excellent opportunity for the development of specific probes for its detection in vivo.
RDP has been extensively analyzed with respect to its catalytic mechanism and inhibition kinetics by a variety of synthetic inhibitors.2-4 The crystal structure of human renal dipeptidase showed it to be a homodimer with each subunit consisting of a 369 amino acid residue peptide (42 kDa).5 RDP is a zinc-containing hydrolytic enzyme that shows preference for dipeptide substrates with dehydro amino acids at the carboxyl position. Morover, it can accommodate substrates with both D- or L-amino acids at that position, providing an excellent opportunity for the development of specific probes for its detection in vivo.6 α-Aminophosphinic acids, the phosphorous analogues of natural occurring α-aminocarboxylic acids, have received increasing interest in medicine7 and synthetic organic chemistry.8-10 The crystal structure of RDP-cilastatin complex5 has demonstrated that the dipeptidyl moiety of cilastatin is sandwiched between the negatively charged and positively charged sidewalls. Both ends of the moiety are clamped tightly by hydrophobic interactions. Certain aminophosphinic acid derivatives bind to the active site of RDP similar to dipeptides.12 
Dehydropeptide analogs whose scissile carboxamide has been replaced with a PO(OH)CH2 group have been found to be potent inhibitors of the zinc protease dehydrodipeptidase 1 (DHP-1 renal dipeptidase, EC 304.13.11). α-aminophosphinic acids bearing a hydrophobic side chain have been found to inhibit APN in the 10−7 molar range. Phosphinate analogs have been reported for inhibition of enzymatic activity of VanX.
There is a continuing need in the art for compounds which are useful for diagnosis and therapy of cancers.